Increased inhaled corticosteroids for treating acute asthma exacerbations

Asthma is characterized by chronic airway inflammation and hyper-responsiveness to a variety of triggers. Patients experience symptoms including dyspnoea, chest tightness, cough and wheeze.1 Asthma severity is defined by the treatment required stepwise in the Global Initiative for Asthma guidelines.2 Asthma affects 8 million adults and children (12% of the population) in the United Kingdom.3 Asthma attacks are a common reason for emergency primary care or hospital visits. Oral corticosteroids are the main treatment shown to shorten acute asthma attacks. Numerous studies have looked at the impact of alternative early interventions in the community on the clinical course of asthma attacks. This Cochrane review explores the clinical effectiveness and safety of increased versus stable doses of inhaled corticosteroids (ICS) as part of a patient-initiated action plan for the home management of exacerbations in children and adults with persistent asthma.4 Increased versus stable doses of inhaled corticosteroids for exacerbations of chronic asthma in adults and children. This is an abstract of a Cochrane review published in the Cochrane Database of Systematic Reviews 2022, Issue 9. (see www.cochranelibrary.com for information). Cochrane reviews are regularly updated as new evidence emerges and in response to feedback, and the Cochrane Library should be consulted for the most recent version of the review. People with asthma may experience exacerbations, or “attacks,” during which their symptoms worsen and additional treatment is required. Written action plans sometimes advocate a short-term increase in the dose of inhaled corticosteroids (ICS) at the first sign of an exacerbation to reduce the severity of the attack and to prevent the need for oral steroids or hospital admission. To compare the clinical effectiveness and safety of increased versus stable doses of ICS as part of a patient-initiated action plan for the home management of exacerbations in children and adults with persistent asthma. We searched the Cochrane Airways Group Specialised Register, which is derived from searches of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and CINAHL (Cumulative Index to Nursing and Allied Health Literature), and handsearched abstracts to 20 December 2021. We also searched major trial registries for on-going trials. We included parallel and cross-over randomized controlled trials (RCTs) that allocated people with persistent asthma to take a blinded inhaler in the event of an exacerbation which either increased their daily dose of ICS or kept it stable (placebo). Two review authors independently selected trials, assessed quality and extracted data. We reassessed risk of bias for all studies at the result level using the revised risk of bias tool for RCTs (Risk of Bias 2), and employed the GRADE approach to assess our confidence in the synthesized effect estimates. The primary outcome was treatment failure, defined as the need for rescue oral steroids in the randomized population. Secondary outcomes were treatment failure in the subset who initiated the study inhaler (treated population), unscheduled physician visits, unscheduled acute care, emergency department or hospital visits, serious and non-serious adverse events, and duration of exacerbation. This review update added a new study that increased the number of people in the primary analysis from 1520 to 1774, and incorporates the most up-to-date methods to assess the likely impact of bias within the meta-analyses. The updated review now includes nine RCTs (1923 participants; seven parallel and two cross-over) conducted in Europe, North America, and Australasia and published between 1998 and 2018. Five studies evaluated adult populations (n = 1247; ≥15 years), and four studies evaluated child or adolescent populations (n = 676; <15 years). All study participants had mild to moderate asthma. Studies varied in the dose of maintenance ICS, age, fold increase of ICS in the event of an exacerbation, criteria for initiating the study inhaler and allowed medications. Approximately 50% of randomized participants initiated the study inhaler (range 23% to 100%), and the included studies reported treatment failure in a variety of ways, meaning assumptions were required to permit the combining of data. Participants randomized to increase their ICS dose at the first signs of an exacerbation had similar odds of needing rescue oral corticosteroids to those randomized to a placebo inhaler (odds ratio (OR) 0.97, 95% confidence interval (CI) 0.76 to 1.25; 8 studies; 1774 participants; I2 = 0%; moderate quality evidence). We could draw no firm conclusions from subgroup analyses conducted to investigate the impact of age, time to treatment initiation, baseline dose, smoking history and fold increase of ICS on the primary outcome. Results for the same outcome in the subset of participants who initiated the study inhaler were unchanged from the previous version, which provides a different point estimate with very low confidence due to heterogeneity, imprecision and risk of bias (OR 0.84, 95% CI 0.54 to 1.30; 7 studies; 766 participants; I2 = 42%; random-effects model). Confidence was reduced due to risk of bias and assumptions that had to be made to include study data in the intention-to-treat and treated-population analyses. Sensitivity analyses that tested the impact of assumptions made for synthesis and to exclude cross-over studies, studies at overall high risk of bias and those with commercial funding did not change our conclusions. Pooled effects for unscheduled physician visits, unscheduled acute care, emergency department or hospital visits and duration of exacerbation made it very difficult to determine where the true effect may lie, and confidence was reduced by risk of bias. Point estimates for both serious and non-serious adverse events favoured keeping ICS stable, but imprecision and risk of bias due to missing data and outcome measurement and reporting reduced our confidence in the effects (serious adverse events: OR 1.69, 95% CI 0.77 to 3.71; 2 studies; 394 participants; I2 = 0%; non-serious adverse events: OR 2.15, 95% CI 0.68 to 6.73; 2 studies; 142 participants; I2 = 0%). Evidence from double-blind trials of adults and children with mild to moderate asthma suggests there is unlikely to be an important reduction in the need for oral steroids from increasing a patient's ICS dose at the first sign of an exacerbation. Other clinically important benefits and potential harms of increased doses of ICS compared with keeping the dose stable cannot be ruled out due to wide confidence intervals, risk of bias in the trials and assumptions that had to be made for synthesis. Included studies conducted between 1998 and 2018 reflect evolving clinical practice and study methods, and the data do not support thorough investigation of effect modifiers such as baseline dose, fold increase, asthma severity and timing. The review does not include recent evidence from pragmatic, unblinded studies showing benefits of larger dose increases in those with poorly controlled asthma. A systematic review is warranted to examine the differences between the blinded and unblinded trials using robust methods for assessing risk of bias to present the most complete view of the evidence for decision makers. Asthma attacks are a common cause of presentation to primary care or emergency settings; they account for 60,000 hospital admissions and 200,000 bed days a year in the United Kingdom,3 and hence constitute a significant cost to health services. If increased ICS at the start of an attack were to be effective, it would be an attractive option, in terms of costs and feasibility, to include on a personalized asthma action plan. The review included 1774 participants, out of whom 1247 are aged≥15 years and 676 < 15 years. Participants randomized to increase their ICS dose at the first signs of an attack had similar odds of needing rescue oral corticosteroids to those randomized to a placebo inhaler (odds ratio (OR) 0.97, 95% confidence interval (CI) 0.76 to 1.25) (see Figure 1). The study participants were on different doses of maintenance ICS; the fold increase of ICS in the event of an attack, as well as the indications for increasing the ICS inhaler, varied with different studies. Approximately 50% of randomized participants initiated the study inhaler (range 23% to 100%). Both the intention-to-treat and treated-population analyses come with a reduced confidence in the results in view of assumptions made and bias. Adherence to inhalers is suboptimal in practice.5 In a US-based study of children aged 8–16 years with asthma, less than 1 in 10 children had good inhaler technique,6 which may account for why increased ICS may be ineffective in an acute attack. One large trial was excluded from this review as it was non-blinded.7 This pragmatic trial with advice to quadruple ICS at first symptoms of an asthma exacerbation reduced severe attacks (hazard ratio 0.81, 95% confidence interval, 0.71 to 0.92), but increased local oropharyngeal adverse effects. Given the null findings of this Cochrane review, the effectiveness of single maintenance and reliever therapy with combined ICS/long acting beta-2 (β2) agonist in acute asthma attacks8 may be attributable to the symptomatic effect of the β2-agonist. In this review, point estimates for serious and non-serious adverse events were in favour of keeping ICS stable. One of the concerns in promoting increased ICS use in acute asthma in the community is the potential risk of a delay in seeking treatment. The National Review of Asthma Deaths report, “Why asthma still kills” showed that in over 60% of asthma deaths, there were potentially preventable factors identified,9 hence the importance of a review in primary care within 48 working hours of an asthma attack. MR analysed the findings of the Cochrane review and wrote this manuscript. The author thanks Dr Robert Boyle for his guidance in preparing this article. No conflict of interest to declare. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.